Lyme disease involves multiple organs, including the skin, heart, joints and nervous system. Following a tick bite, B. burgdorferi are deposited in the skin of the mammalian host. Spirochetes reside in the dermis for about one week and then spread to many tissues throughout the body. The spirochetes colonize the joints, causing arthritis in both mice and humans. The goal of this proposal is to characterize B. burgdorferi genes important in spirochete dissemination from the skin and colonization of the joints. The identified gene products will then be targeted to interfere with specific phases of the spirochete life cycle. These studies will use the murine model of tick-borne B. burgdorferi infection, which partially mimics human disease, and specimens from patients with well-documented Lyme disease. These data will lead to a greater understanding of how B. burgdorferi gene expression contributes to spirochete infectivity, and suggest new strategies for the prevention and treatment of Lyme disease.